Method for controlling vascular responses

ABSTRACT

A method for producing changes in systemic arterial blood pressure, cerebrospinal fluid pressure and heart rate, as well as producing selective brain hypothermia in animals by irrigating the nasal mucosa. The method includes locally applying a fluid to change the temperature of the region of the face and, hence, the blood drained by the angularis oculi and facial veins. Heat and cold produce opposite effects.

United States Patent 1191 Magilton et al.

[ 1 Aug. 5, 1975 METHOD FOR CONTROLLING VASCULAR RESPONSES [75]Inventors: James H. Magilton; Curran S. Swift,

both of Ames, Iowa [73] Assignee: Iowa State University ResearchFoundation, Inc., Ames, Iowa 22 Filed: Aug. 8, 1973 211 Appl. No.:386,605

Related US. Application Data [63] Continuation-impart of Ser. No.171,575, Aug. 13,

1971, Pat. No. 3,776,241.

[52] US. Cl 128/400; 128/40] [51] Int. Cl. A6 7/00 [58] Field 01' Search128/400, 303.1, 401, 24.1, 128/2 H [56] References Cited UNITED STATESPATENTS 3,074,410 1/1963 Foster 128/400 3.170.465 2/1965 Hermey et a1128/401 3,238,944 3/1966 Hirschhorn 128/400 OTHER PUBLICATIONS J. N.Hayward et al., Brain Research, 16 (1969), pp. 417-440.

J. H. Magilton et al., Journal of Applied Physiology, Vol. 27, No. l, p.18.

J. H. Magilton et al., The Physiologist, Vol. 10, No. 3, Aug. 1967, p.24.

Primary Eraminer-Lawrence W. Trapp Attorney, Agent, or Firm-Dawson,Tilton, Fallon & Lungmus 1 1 ABSTRACT A method for producing changes insystemic arterial blood pressure, cerebrospinal fluid pressure and heartrate, as well as producing selective brain hypothermia in animals byirrigating the nasal mucosa. The method includes locally applying afluid to change the temperature of the region of the face and, hence,the blood drained by the angularis oculi and facial veins. Heat and coldproduce opposite effects.

8 Claims, 12 Drawing Figures PATENTEU AUG 51ers SHEET Fig.4

TABLE I Summarization of pressure and heart rate changes and their timerelationships (CSFP Cerebrospinal fluid pressure; AB? Femoral arterialblood pressure) 1 Number water Mean Max. I Mean Time, Mean Time, HeartRate of Temp. Change in 1 all Trials, all Trials, Changes Trials ChangeAmplitude for the for the for all First Detec- Maximum of Trials, tablePres- Pressure Trails & mmHg 1' sure Change Change to Type of i toAppear, Occur, Change Seconds Seconds csFPi ABP 1 csrp ABP CSFP I ABP i1 1 E Cold I j 12 {5 Dogs 16 to Hot +3 .0 +17. 9 1 14.4 34.0 105 7 193.31 r a T. e 1 Urethan Hot to Anesthesia 16 Cold 2.5 l4.8 8.2 9.7 178.6l33.3 l3 T i i 1 1 Cold i 1 11 13 Dogs 12 to Hot +6. 1 +l8.5 l 20.6 18.2289.3 252. l l O T 1 1 i 1 EMetofane Hot to 1 :Anesthesia 12 Cold -5. ll8.8 80.5 24.0 497. 1 }483. l 1 l J l Cold water temperature was 15 Cand hot water temperature ranged from 45-48 0.

2 Time was measured from the instant the water temperature was changed.

3 Heart rate was not monitored in Experiment 8 (6 trials) 4. increase;

= decrease,- and "O" no change.

TABLE II Temperature data for human subject study. All temperatures(columns 6-12) are in C COLUMN NUMBER e e e 4 2 4 2 fiw 53 n m m m 4. 13 38 u N N o o N o @96 32 .v w T v A Pl 1 1 4 4 4 2 2 l 7 2 4 3 1 2 e e3 1 flx flsk n n mm c 0 0 O 0 e 0 e O 0 O 0 O O O O O 0 o o 0 O 1 2 m mn n N N l muommm cmwz wm R W V Al N .I M 4! Al v a Al 0 R Iv 4 wucwuwwma mm am SHOE MOM 5 7 9 7 4 2 2 9 m m N H How 0 O O 0 l l l O l 4 A Inwmcm u uwz Q: pl Al Al Al Al fixfireuwfic .4 1 52 3 7mm 7mm .3 m2 m 0 OO 0 O 0 0 0 1 0 o O O o 0 O O o O O l 9 m zmsu A A 1 Pk A N N T N EDE XAlb. m. A Ti Al H l O HO 5 1 1L 4 O 8 n 2 5 mm m m w. m nu m w 0 O l l l2 O O 1 8 CESHOU MOM Jv 0 I v 9 v mmcms umz fixfifi 5 5 5 1 .5 5 $1M mi31 7 mmcmnu O O 0 0 0 0 0 0 O O 0 l l O O O m m 0 O l EDE xm w 4 t v v w@WW v v v V fi fifi at .3 A .5 1A3 33 6 wuowwm 44 66 54 65 032 655 54244 43 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 5 GHw LR LR LR LR LRALRA LRA LR LR 4 m F M M M F M F M M 3 953 m* w* m ml" w* %1 m @w m 2mmes VEE R R R R R R R R R Hm EBZ l UUUWDDW l 2 3 4 5 6 7 8 9 leftright,

Notes:

left angularis oculi vein R right angularis oculi vein A medianantebrachial vein 3 8 9 7, 7 9 O PATENTED M19 SHEET 4 Fig. 58

TABLE II (continued) 4. In laboratory with lights out and surroundingsas quiet as possible.

5. temperature decrease,- temperature increase.

6. Differences obtained from entries in columns 7 and 9.

METHOD FOR CONTROLLING VASCULAR RESPONSES RELATED APPLICATIONS This is acontinuation-in-part application of subject matter disclosed in ourcopending application Ser. No. 171,575, filed Aug. 13, 1971, and now US.Pat. No. 3,776,24l for System and Method for Controlling VascularResponses." We claim benefit of that filing date for common subjectmatter not claimed therein, and we incorporate herein by reference thesubject matter of that application not carried over to this application.

BACKGROUND OF THE INVENTION 1. Field of the lnvention The presentinvention relates to a method for producing: l. cardio-vascular changes;and (2) selective brain hypothermia in a mammal by locally irrigatingthe surface facial region which overlies and is drained by the angularisoculi and facial veins. The irrigation is done with a fluid of knowntemperature; and it is preferably brought into contact with the nasalmucosa of the animal for heat transfer although the fluid may alsocontact the facial skin in the region drained by the facial veins andthe angularis oculi vein.

It has been suggested that the hazards of cardiovascular surgery andcerebral edema following brain trauma would be greatly reduced if thetemperature of the brain were reduced (hypothermia) within controlledlimits. Three reasons for this suggestion are that: l oxygen consumptionin the brain decreases almost linearly with lowering of the temperatureunder controlled conditions; (2) cerebral blood flow and mean systemicarterial blood pressure decrease while cerebrovascular resistanceincreases with hypothermia; and (3) cerebral blood flow and brain volumechange in the same direction. Thus hypothermia would reduce the bloodflow to the brain, thereby reducing brain volume, and increase thetolerance of the brain to hypoxia.

An early method of reducing the temperature of the brain includedcirculating a refrigerated solution through a metal capsule (withconnecting tubing) which had been placed in the brain. Total bodyhypothermia, as an indirect means of cooling the brain, replaced thisearly method. Total body hypothermia has certain disadvantages includingthe need for a large amount of equipment to maintain the lowtemperature, and the tendency of the heart to go into fibrillation atlow body temperatures. Attempts have been made, therefore, to produceselective brain hypothermia--that is, lowering of the brain temperaturewithout lowering the temperature of the rest of the body significantly.One suggested method of selected brain hypothermia is to cool theesophagus, as reported in the technical documentary port No.SAM-TDE-63-l9 of the USAF SCHOOL OF AEROSPACE MEDICINE, AerospaceMedical Division, Brooks Air Force Base, Texas. Attempts have also beenmade to achieve selective brain hypothermia by cooling blood destinedfor the head in an extra-corporeal cooling system. The objections tothis approach have caused it to be abandoned. At present there is nosurgical technique to our knowledge that is commonly accepted for theselective inducement of brain hypothermia.

2. Published Work An abstract of a paper given by us was published inThe Physiologist, Vol. 10, No, 3, August, 1967, in which we reportedachieving cooling of the brain of the canine by irrigating the alarfolds of the maxilloturbinates with water having a temperature of l2.0C. We reported that the venous blood passing from the alar folds intothe cavernous sinus cooled the arterial blood passing to the brain byway of the latter sinus. This arterial blood absorbed heat from thebrain after passing through components of the Circle of Willis and theirdistributing vessels. We postulated at the time of this work that twoseparate heat exchange mechanisms were involved one, which we called theexternal heat exchange system, is located in the alar fold of themaxilloturbinate and cools blood which flows into the cavernous sinus byway of the angularis oculi vein, and the second, which we called theinternal heat exchange system, is in the cavernous sinus where heat istransferred from the warm arterial blood destined for the brain to thecooler venous blood in the cavernous sinus.

In a subsequent article of Hayward and Baker entitled A ComparativeStudy of the Role of Cerebral Arterial Blood in the Regulation of BrainTemperature in Five Mammals, published in Brain Research, Vol. 16, p.4l7, 1969, work was reported in this area on different species ofmammals, ,and as a result, the authors classified their subjects intotwo broad categories: l those of the internal carotid" artery type whichincludes the monkey and the rabbit and is characterized by having asingle large vessel passing through the cavernous sinus therebyproviding a flow pathway from the common carotid artery to the Circle ofWillis; and (2) the carotid rete" type which is characterized by havingmore than one communicating vessel from the common carotid artery to theCircle of Willis: (1) via the cavernous sinus as in the dog and sheep;and (2) in close proximity to a venous plexiform network in cats.

Based on their experiments, these researchers concluded that heatexchange occurs between the cooler venous blood in either the cavernoussinus (for the dog and sheep) or the venous plexiform network (in thecase of the cat) and the warmer arterial blood only in those animals ofthe carotid rete" type. Further, these researchers believed themselvesto have demonstrated that for animals having a single internal carotidartery conducting blood through cavernous sinus, there was no heatexchange at the base of the brain. These studies concluded that this wasa major difference between the two classifications. Persons skilled inthe art will appreciate that when reference is made to an animal havinga single internal carotid artery reference is made to only one of thetwo internal carotid arteries which, due to bilateral symmetry, occur ineach such animal.

The results of our further experimental work on the physiological heatexchange systems for controlling the brain temperature of a dog arereported in an article appearing in the IEEE Conference Record, FifthAnnual Rocky Mountain BioEngineering Symposium 1968 entitled Descriptionof Two Physiological Heat Exchange Systems for the Control of BrainTemperature and in an article published in the Journal of AppliedPhysiology, Vol. 27, No. l, p. 18, I969, entitled Response of VeinsDraining the Nose to Alar-Fold Temperature Changes in the Dog.

SUMMARY As a result of our experimentation, including work performed onman and on horses each of which have a single large carotid arteryleading from the common carotid artery and passing through the cavernoussinus to the Circle of Willis, we believe we have demonstrated thatselective brain hypothermia can be induced by locally irrigating thesurface area of the facial region or nasal passage drained by theangularis oculi and facial veins in animals with a single internalcarotid artery, as well as those with a carotid rete, with cold water.The surface area as thus stated includes the facial skin in this regionas well as the nasal mucosa, either one of which or both may beirrigated.

This, of course, is contrary to the conclusions reached by thedistinguished researchers, Hayward and Baker, mentioned above. As aresult of further experimentation with dogs, we have been able to inducechanges in cerebrospinal fluid pressure, systemic blood pressure, andheart rate by irrigating the nasal mucosa. That is, we have been able toselectively increase the cerebrospinal fluid pressure, systemic bloodpressure and heart rate by irrigating the tip of the nose with hotwater, and we have produced reductions in cerebrospinal fluid pressure,systemic blood pressure and heart rate by irrigating the tip of the nosewith cold water. Thus, we believe we have demonstrated a method ofcontrolling blood flow to the brain of a mammal.

While not limiting the effect of our invention, we postulate that thereare two principal physiological mechanisms or systems which have abearing on the brains temperature. One such system we call the venoustemperature control system; and it regulates the cooling of the venousblood destined for the cavernous sinus. The second system we call thecardioarterial control system; and it acts in a manner to assist thevenous temperature control system in regulating brain temperature. Thatis, when the venous control system has reached the limits of itscapability to cool the venous blood, the cardioarterial system willfurther influence the rate of heat exchange occurring between arterialand venous blood in the cavernous sinus by apparently altering arterialblood flow through the sinus. We believe the arterial flow through thecavernous sinus will be altered as a result of the changes in heartrate, systemic arterial pressure and cerebrospinal fluid pressure whichwe have demonstrated in our work.

When the regulatory effects of both of these physiological systems areoverridden by irrigating the nasal mucosa with a medium of adequatelycold temperature, one can induce selective brain hypothermia and alterthe flow of cerebral arterial blood, even in man, having a singlecarotid artery.

Although the invention is not so limited, some of the clinicalapplications, as alluded to above, include selectively reducing thetemperature of the brain without causing corresponding low temperaturesin the remainder of the body. This has an advantage in heart surgery dueto the fact that the oxygen requirement of the brain is reduced linearlywith reduction in brain temperature. Therefore longer interruptions incerebral blood flow can be tolerated. In addition, the heart can bemaintained at near normal body temperature which reduces the propensityof this organ to go into fibrillation when manipulated in surgery.

Other features and advantages of the present invention will be apparentto persons skilled in the art from the following detailed description ofa preferred em bodiment accompanied by the attached drawing whereinidentical reference numerals will refer to like parts in the variousviews.

THE DRAWING FIG. 1 is a pictorial diagram of the head of a subject dogshowing the irrigation of the nose and the placement of temperaturesensors on the angularis oculi veins.

FIG. 2 is a graph illustrating changes in cerebrospinal fluid pressureand arterial blood pressure resulting from the irrigation; and

FIGS. 3A-3G are graphs illustrating the various vascular responsesduring irrigation.

DETAILED DESCRIPTION We have shown in our laboratory that temperaturealone can produce changes in the cardio-arterial system of animals whichappear to vary cerebral blood flow and cerebral temperature in a mannerthat has not been reported elsewhere. The cardio-arterial changes areseen as a change in systemic arterial blood pressure (ABP),cerebrospinal fluid pressure (CSFP) and heart rate (HR). Thesecardio-arterial changes were induced by changing the temperature of thevenous blood destined for the cavernous sinus by irrigating the alarfold of the maxilloturbinate. These cardio-arterial changes were such asto indicate that an increase in cerebral blood flow occurred when thetemperature of the nasal mucosa was increased by irrigation with warmwater, and a decrease in cerebral blood flow was indicated when thenasal mucosa was irrigated with cold water. Further, thesecardio-arterial changes appear to be brought about by an automaticreflex uniquely responsive to temperature. That is, the usual responseto auto nomic manipulation is such as to maintain a constant cerebralblood flow; wereas the autonomic response to the temperature changes weemployed appears to have altered cerebral blood flow (heat making theflow increase and cold making it decrease). Furthermore, thesecardio-arterial changes have occurred independently of carbon dioxide,oxygen and pH levels of the arterial blood, as has already beenreported.

We believe that brain temperature regulation is accomplished through theagency of two physiological systems. The first system provides forirrigating or circulating the surface of the nasal mucosa (morespecifically, the alar fold of the maxilloturbinate) with an externalmedia such as water, air or other gas. A portion of this temperatureconditioned blood flows to the cavernous sinus where it bathes arterieswhich conduct blood to the brain. In our early work this system wasreferred to as the external heat exchange mechanism." In our presentwork it is referred to as the venous temperature control system (VTCS).The second system involves control of the blood flow in the arteriesjust mentioned which are being bathed in the venous blood in thecavernous sinus which, in turn, has been temperature conditioned at thesite of the external heat exchange mechanism. In our early work thissystem was referred to as the internal heat exchange mechanism; in ourpresent work it is referred to as the cardioarterial control system.

VENOUS TEMPERATURE CONTROL SYSTEM Intracerebral temperature gradientsare basically de pendent upon the rate of removal of heat from the brainby arterial blood. This arterial blood is cooled by the flow of heatfrom the arterial blood to venous blood in the cavernous sinus. Thetemperature of the venous blood, in turn, is regulated by what isreferred to herein as the venous temperature control system (VTCS). Thissystem functions in two ways. The first includes a transfer of heat fromthe vessels in the nasal mucosa (that is, the alar fold of themaxilloturbinate) to (or from) the irrigating water or circulating airor other gas which contacts the nasal mucosa. The second manner in whichthe venous temperature control system works is to regulate thedifferential blood flow from the vessels in the nasal mucosa via thedorsal nasal veins to the angularis oculi veins on the one hand, and thefacial veins on the other hand. The blood entering the angularis oculiveins flows through the ophthalmic veins to the cavernous sinus where itbathes arterial blood destined for the brain. The blood entering thefacial veins by posses the cavernous sinus.

We have established through experiments the existence of a feedbackcontrol pathway from the brain to the venous temperature control system.We selected man as the experimental subject in an attempt to demonstratethis feedback control. The reasons we selected man were: (I) theanatomical arrangement of the necessary structures is similar to that inthe dog; (2) the subjects would be fully cooperative and would be ableto perform precise mental tasks; and (3) previous experimental work (5)has shown that mental activity increases metabolic rate which, in turn,increases heat production. As a result of our work, physiologicalevidence that the venous temperature control system is involved in braintemperature regulation was shown. It was found that mental activity(subtracting from 5000 by sevens as fast and accurately as possible) wasaccompanied by adjustments in the venous temperature control systemwhich resulted in changes in the temperature of the angularis oculiveins (the assumption is made that an increase in metabolism in an organis ac companied by an increase in the temperature of the organ Furtherevidence pointing to the involvement of the venous temperature controlsystem in brain temperature regulation was seen in the unanesthetizedsheep where an increase in the temperature of the reticular formationwas accompanied by a cooling of the nasal mucosa. In this case anincrease in the temperature changes occurring in the brain demonstratesthe adjusting of the vanous temperature control system to obtain optimumbrain temperature.

There is also evidence that adjustments which occur in the venoustemperature control systems do not depend upon conscious activity. Forexample, in dogs under sodium pentobarbital anesthesia, uniformity wasfound to be lacking in the shape of the temperature curves between theangularis oculi and facial veins on the homolateral side. Thesevariations in temperatures indicate variations in blood flow in therespective veins, and it is therefore evident that the homolateralreflex pathways involving the venous temperature control system arefunctional under anesthesia. Additionally, not only are the reflexpathways between the veins on the homolateral side intact (angularisoculi and facial) but also, the reflex pathways between veins of thevenous temperature control system on opposite sides are intactand.functional (evidenced by lack of uniformity between the temperaturesof the right and left angularis oculi veins).

These variations in blood flow between the angularis oculi and facialveins on the same side and between the angularis oculi veins on oppositesides is considered important because blood entering the angularis oculivein enters the cavernous sinus by way of the ophthalmic vein, whereasblood entering the facial vein passes into the external maxillary andthen into the external jugular vein, thus bypassing the cavernous sinus.It is evident then that the blood entering the angularis oculi vein isinvolved with heat transfer (consequently braim temperature regulation)between arterial blood destined for the brain and venous blood in thecavernous sinus, whereas the blood entering the facial vein is not.

We have found evidence that autonomic control exists at the level of theangularis oculi and facial veins not only in the time-response variationof these veins between coldand hot-water irrigation as will bediscussed, but also in the response of the angularis oculi veins to theclamping of the facial veins.

The mode of action of the autonomic innervation to the vessels in thevenous temperature control system is considered important because of thesystems involvement with brain temperature regulation, as previouslymentioned. In this regard, the nasal vessels possess unique neuralcharacteristics which indicate that their response to the autonomicstimulation is different from the responses of vessels in other parts ofthe body to autonomic stimulation. For example, there is reason tobelieve that the frequency of sympathetic impulses necessary to maintainvascular tonus and to mediate reflex vasoconstriction is different inthe nasal vessels than in vessels in other parts of the body. If this isthe case, then the sympathetic nervous systemcould exert differentialcontrol over the nasal veins on the one hand and the dorsal nasal,angularis oculi, and facial veins on the other hand, by means ofvariation in the impulse frequency.

Another example of the uniqueness of neural characteristics of arteriesand veins in the nasal passage is that beta-adrenergic receptors cannotbe physiologically demonstrated in them. This means that in situationsof high emotional stress, accompanied by adrenergic dominance, the onlyresponse attainable is constriction of the arteries and veins in thenasal passage, resulting in an increase in the size of the lumen of thenasal passage. This agrees with work done by others wherein adrenalinwas injected intravenously and produced a marked constriction of thevessels lining the nasal passage. This constriction of the vesselslining the nasal passage. This constriction results in more cooling ofthe venous blood in the venous temperature control system due to anincrease in the rate of heat transfer occurring from the vessels to theambient air. This is probably due to the larger heat transfer area, andthe slower rate of flow in the veins lying immediately below the mucosalsurface.

lf the assumption can be made that emotional stress situations are oftenaccompanied by an increase in heat production in the brain due to anincrease in mental activity, then a situation could develop duringemotional stress where an increase in brain temperature would beaccompanied by a decrease in the efficiency of the cooling system forthe brain.

As already mentioned, we believe that brain temperature regulation isaccomplished by the interaction of two systems: (I) cooling of venousblood destined for the cavernous sinus (the venous temperature controlsystem described previously) and (2) control of the cerebral blood flowthrough the cavernous sinus by a cardio-arterial control system. Themore efficient the venous temperature control system is, the less thecardioarterial control system will have to alter cerebral blood flow inorder to obtain optimum brain temperature. Some of the conditions whichwill determine the efficiency of the venous temperature control systemare: (l environmental temperature, (2) environmental humidity, and (3)nasal respiratory rate andamplitude, and (4) emotional stress.

Cardio-arterial Control System If the ambient temperature is excessivelyhigh, heat transfer from the nasal vessels to the inhaled ambient air isreduced and cardioarterial adustments occur (i.e., an increase in heartrate (HR), an increase in systemic arterial pressure (ABP), and anincrease in cerebrospinal fluid pressure (CSFP)), which are evidence ofan increase in cerebral blood flow. The opposite cardio-arterialadjustments occur when the temperature is excessively low. In furtherexplanation, the venous temperature control system, by itself, is ableto regulate brain temperature as long as ambient temperature remainswithin as yet undetermined limits of hot and cold. Consequently. it isonly when these limits of heat and cold are exceeded that thecardio-arterial control system comes into play by adjusting cerebralblood flow in an effort to complement the venous temperature controlsystem. The role of the cardioarterial control system, when the hot andcold temperature limits are exceeded, is that of obtaining optimum braintemperature regulation. These relationships have been verified byexperimental work conducted in our laboratory. Using running water toobtain maximum heat transfer both toward the blood in the nasal vessels(with 42C50C water irrigation) and away from the blood in the nasalvessels (with C water irrigation), we were able to obtain thecardio-arterial adjustments to be described below in connection withFIG. 3.

Humidity is another factor influencing the amount of heat transferoccurring in the venous temperature control system. In this regard,humidity affects the amount of cooling which occurs on the mucosalsurface. For instance, the higher the humidity, the less the heat lossoccurring from the mucosal surface as a result of evaporation. For thisreason, the limits of ambient heat and cold, beyond which thecardio-arterial control system comes into play to complement the venoustemperature control system, are partially determined by humidity. Webelieve that, under normal conditions, the resultant loss of efficiencyin heat transfer in the venous temperature control system due tohumidity would be compensated for by the cardio-arterial adjustmentspointing toward increasing blood flow as previously described.

The temperature of the blood in the venous temperature control systemcan be lowered by increasing the nasal respiratory rate and amplitude inman. Also, the CSFP (a part of the cardio-arterial control system) canbe lowered to zero in man by increasing respiratory rate and amplitudeunder conditions which make it unlikely that blood gas levels wouldcompletely account for the reduction, Although different procedures wereused, similar results to those in man, i.e., lowered blood temperaturein the venous temperature control system during deep respiration andvice versa and lowered CSFP during deep respirations, were obtained inour laboratory using the dog. in man the temperature was lowered byincreasing the respiratory rate and amplitude, whereas in the dog it waslowered by irrigation of the nasal mucosa with 15C tap water. In bothspecies it appears that the cold temperature limit for regulation ofbrain temperature by the venous temperature control system had beenexceeded thereby activating the cardioarterial control system. Also, inboth species some degree of feedback control of the two systems wasremoved in man by voluntary respirations and in the dog by irrigationunder anesthesia. This assumption was supported by the fact that thechanges in CSFP seen in both species were due to over-cooling of thevenous blood in the venous temperature control system.

The interaction between the venous temperature control system and thecardio-arterial control system to obtain optimum brain temperature canbe manipulated and changed in useful ways. First, as a method forinducing differential brain hypothermia, the temperature of the blood inthe venous temperature control system can be lowered to a level at whichnot even the cardioarterial control system can adequately compensate,and brain temperature is thereby lowered. Among the clinical benefitsaccruing this differential brain hypothermia are: (a) a decrease incerebral metabolic rate allowing for extended vascular interruptions tothe brain; (b) infarction can be prevented or rendered clin icallyundetectable when the middle cerebral artery is ligated during wholebody immersion in ice water; and (c) no cellular inflammatory reactionto injury is noted, and development of cerebral edema can be suppressedas long as the brain remains cold.

Additionally, these two control systems can be manipulated so as toreduce cerebral blood flow (along with a decrease in ABP, CSFP, and HR)as noted during the cooling of the venous blood destined for thecavernous sinus. This would: (a) facilitate hemostasis during brainsurgery and (b) facilitate surgical procedures by reducing brain volumeand intercranial pressure.

It appears that simulating the cardio-arterial control system withtemperature invokes a unique autonomic response in the circulatorysystem, i.e., increase in AB? (vasoconstriction) and an increase in CSFP(vasodilatation) with heat, and the opposite ABP and CSFP responses withcold. This autonomic response to temperature is unique in that it is notthe all-ornothing response usually seen with autonomic stimulation,i.e., increase in ABP (vasoconstriction) and a decrease in CSFP(vasoconstriction) with epinephrine; and the op posite ABP and CSFPresponses with artificial stimulation of the vagus.

In this regard, it is recognized that alpha and beta adrenergicreceptors make it possible for the adrenergic nerves to dilate bloodvessels as well as to constrict them. However, this dual response hasnot been demonstrated for the cholinergic nerves to our knowledge,consequently vasoconstriction would have to be the result of adrenergicnerve stimulation. In view of this, the constriction of cerebral vesselsduring cold water irrigation of the nasal mucosa (if due to autonomicstimulation) would have to be due to adrenergic action. There isdefinite evidence, on the other hand, that the adrenergic nerves are notresponsive for the extracranial vasodilatation during cold waterirrigation (decrease in ABP). That is, in our laboratory cold waterirrigation was accompanied by excessive lacrimation which is consideredto be a response to cholinergic stimulation.

The all-or-nothing response of the blood vessels to stimulation of theautonomic nervous system for epinephrine (constriction) and electricalstimulation of the vagus (dilatation) appears to be for the purpose ofmaintaining a constant cerebral blood flow. The response of theautonomics to the stimulus of temperature applied to the cardio arterialcontrol system, on the other hand, appears to be for the purpose ofvarying blood flow (increase in ASP, HR and CSFP from heat indicating anincrease in flow; decrease in ABP, HR and CSFP from cold indicating adecrease in flow).

Turning now to FIG. 1, the nature of our experiments will be described.In our early experiments, the subject was a dog, only the head of whichis illustrated. Resting before the nose of the dog is a base plategenerally designated by reference numeral 10 in which there are embeddedan input lead 11 and a bifurcated output conduit 12 leading into thenose of the dog as illustrated. The input conduit 11 is connected to asource of cool water (not shown) or other cooled fluid such as air, andthe distal ends of the bifurcated output conduit l2, 12 are locatedadjacent the tip of the dog's nose and oriented so as to direct a streamof the cool water principally onto the alar folds of the dog's nose. Thepressure of the water passing through the output conduits 12, 12 is onlysufficient to cause an upward flow of water of only a few inches.

Leading from the alar folds of the dog are two angularis oculi veins, aleft and a right vein, which communicates venous blood from the alarfolds into cavernous sinus of the dog. Placed adjacent the left andright angularis oculi veins are first and second thermistors designatedrespectively 13 and 14, and these are arranged by means of wires 16 and17 respectively to monitor the temperature of the blood flowing in theleft and right angularis oculi veins of the dog.

Experiments Eight dogs weighing from 30-4O pounds were anesthetized andplaced in ventral recumbancy (as illustrated) with the head elevated bysecuring the zygomatic arches to a metal rack with bone screws. The longaxis of the head was held at a 45 angle in relation to the long axis ofthe neck by ventral traction of the anterior extremity of the upper jaw.

Five dogs (Exps. 8, 9, l0, 1 l, 12) were anesthetized with 20 percentUrethan (ethyl carbamate manufactured by Matheson, Coleman and Bell ofEast Rutherford, New Jersey) in distilled water given intravenously toeffect. Three dogs (Exps 13, 14, 15) were first given Surital (sodiumthiamylal manufactured by Parke, Davis & Co. of Detroit, Mich.) 4percent intravenously. Anesthesia was taken continued with Metofane(methoxyflurane manufactured by Pitman-Moore of Indianapolis, Indiana)in a Heidbrink Model 2000 closed circle anesthetic gas machineEndotracheal catheters were employed in all experiments.

Respiration was monitored only in experiments 8 through 12 by athermistor needle probe placed in the endotracheal catheter. Bodytemperature was monitored via a therminstor rectal probe and a Tele-Thermometer (Yellow Springs Instrument Co., Yellow Springs, Ohio). Thetemperature of the right and left angularis oculi veins were monitoredby needle thermistors placed on the deep face of the veins near themedial canthus of the eye as shown at 13 and 14 of FIG. 1. Thetemperature of the water irrigating the end of the nose was monitored bya thermistor placed in the water hose 10 at about 4 inches from the openend of the irrigating tube 12, 12 which, in turn, were placed in thenostrils as illustrated. The systemic arterial pressure was measured byconnecting a fluid-filled cannula from the femoral artery to a StathamP23BC pressure transducer. The cerebrospinal fluid pressure was measuredthrough a l9-gauge needle inserted into the cisterna magna attached by afluid-filled cannula to a Statham PZBBC pressure transducer. The EKG wasalso sensed and processed by a Grass Model 7P4AB Tachograph for heartrate indication. All of the transduced parameters along with a markingsignal were recorded on a ten-channel Grass Model 7 ink-writingrecorder. The two pressure signals and the heart rate signal wereelectrically damped to provide a write-out of means values.

The experimental procedure carried out with each animal was as follows.After anesthesia and attachment to the rack, a 10-1 5 minute rest periodwas allowed in order to establish resting or normal values of allrecorded parameters. Then the tip of the nose (with special emphasisupon the alar fold of the manilloturbinate) was irrigated with coldwater (15C.) for 10-15 minutes. The experimental trials then followed. Atrial is defined as one change in irrigating water temperature (fromcold to hot or from hot to cold). The hot water temperature was in therange of 45-48C.

After completion of the trials the brains were probed. The probe on theright side was inserted after a maximum increase in both cerebrospinalfluid pressure and systemic pressure had been obtained during hot waterirrigation. The probe on the left side was inserted after the right sideprobe had been withdrawn and after a maximum decrease in both pressureshad been obtained during cold water irrigation.

A 4-inch long 25-gauge needle was employed as the brain probe. It waspassed through holes 2 mm in diameter drilled through the skull with adental burr just posterior to the frontopariental suture and 1 cmlateral to the dorsal midline on both the right and left sides. Theprobe was passed ventrally through the dura mater and brain until itimpinged on the bone at the base of the skull and then withdrawn ameasured distance.

When the physiological aspects of the experiments were completed, thebrains were removed from six dogs. Three dogs (Exps. 10, ll, 12) wereremoved from the rack, placed in lateral recumbancy, exsanguinated, andembalmed with 10 percent formalin solution through the common carotidartery. The probe tracts in the brains were then exposed andphotographed. Three dogs (Exps. l3, l4, 15) were exsanguinated whilestill in the rack and comparisons of the two sides of the unembalmedbrain were made by visual inspection and then photographed.

in all of the fifty-six reported trials during which the temperature ofthe irrigating water was increased or decreased, the cerebrospinal fluidpressure (CSFP) and femoral arterial blood pressure (ABP) always increased or decreased respectively. In the fifty trials in which heart(HR) was monitored, this parameter, with a few exceptions, also showedan increase or decrease with a respective increase or decrease inirrigating water temperature. The above responses when applied to twosucceeding trials (cold to hot and back to cold) are defined by theauthors to be examples of overall normal responses. Furthermore, thetemperature of the angularis oculi vein always followed in the samedirection as the water temperature.

The significant results are summarized in Table I. The table indicatesthat there were 32 trials carried out under Urethan-chloroloseanesthesia and 24 with Metofane anesthesia. Also, there were 28cold-to-hot and 28 hot-to-cold trials. The pressure and time entries inthe table are the mean values obtained in each type of trial.

FIG. 2 graphically illustrates the pressure and time relationshiprecorded in Table I. In FIG. 2, the abscissa is time; and the ordinateis pressure. The results of hot and cold water irrigation are shownabove and below the absicca respectively. The solid lines representchanges in cerebrospinal fluid pressure, and the dashed lines representchanges in femoral arterial blood pressure. Time was measured asstarting when the water temperature change was detected by thethermistor in the water-conducting tube. The beginning point of eachline. which lies on the time axis, is the mean time for the firstdetectable pressure change to occur. The vertical coordinate of the endpoint of each line is the means maximum change in pressure thatoccurred. Finally. the horizontal coordinate of the end point of eachline is the mean time it took for the maximum pressure change to appear.

FIG. 2 illustrates the following points:

Whether the irrigating water temperature was hot or cold:

I. All pressure levels reached their maximum excursions sooner underUrethan-chlorolose anesthesia.

2. The rate of change of pressure (slope of each line) was greater inabsolute value with Urethan anesthesia.

3. In 3 of the 4 pairs of lines (paired by type of pressure), theinitial change in pressure came sooner when Urethan-chloroloseanesthesia was used.

4. Greater pressure changes were noted with Metofane anesthesia.

Regardless of the type of anesthesia used:

I. All pressure levels reached their maximum excursion sooner under hotwater irrigation (change from cold to hot).

2. Hot water irrigation caused greater pressure changes to occur in allcases except in the ABP measurement under Metofane anesthesia.

3. The rate of change of each pressure was greater in absolute valuewith hot water irrigation.

In our experiments the responses of the cardioarterial system totemperature changes in the brain were such that the pressure andresistance relationships seen in the classical response to autonomicstimulation did not apply. That is, a decrease in both cerebrospinalfluid pressure (CSFP) and heart rate (HR) and an increase in femoralarterial blood pressure (ABP) usually seen during sympatheticstimulation; and an increase in CSFP and HR along with a decrease of ABPusually seen in vagal stimulation did not usually occur.Vasoconstriction (sympathetic), vasodilatation (vagus) and changes inheart rate are manifestations, both intracranially and extracranially,of autonomic stimulation. These responses are (among otherpossibilities) aimed at maintaining a more or less constant cerebralblood flow. The nature of the response of the arterial system totemperature changes in our experiments, however,

are interpreted to have changed cerebral blood flow. As cerebralresistance increased (vasoconstriction decrease in CSFP), ABP did notincrease, but instead it decreased. Inasmuch as heart rate (HR) alsodecreased, indications are that the flow of blood to the braindiminished when the alar fold of the maxilloturbinate was cooled.Further. when the temperature of the alar fold was increased byirrigation with warm water CSFP, ABP and HR increased, indicating anincreased flow of blood to the brain. We therefore conclude that bycooling the nasal mucosa to a degree such that neither the venoustemperature control system nor the cardio-arterial control system wasable to compensate, the temperature of the brain was lowered. Thelowering of the brain temperature was accompanied by cardioarterialchanges which indicated that blood flow to the brain was being reduced.

It appears that there are two routes over which the brain receivesinformation relating to temperature changes originating at the nose. Inone of the above cited reports, we noted that when the irrigating waterwas changed from hot to cold, the temperature response in the region ofthe posterior communicating artery lagged the response of the angularisoculi vein by 6 seconds. In the present series of experiments, changesin CSFP (FIG. 3c), ABP (FIG. 3B), and HR (FIG. 3A) always lagged thetemperature changes in the irrigating water (FIG. 3E) and usually laggedtemperature changes in the angularis oculi veins (FIG. 3F). FIG. 3D is acommon time marker for all the graphs of FIGS. ISA-3C, and 3E-3G. In oneexperiment, however, pressure and rate changes occurred beforetemperature changes were observed in the angularis oculi veins. There isa possibility in view of this that in some cases the brain is receivingstimuli by a route other than the venous return route from the nose tothe cavernous sinus. The time lag between the changes in water temperature and the changes in pressures and heart rate (3-5 seconds),considering that water temperature was being measured in the conductinghose 4 inches before reaching the nose, suggests that the second routeis a nerve pathway.

Body temperature varied slightly with the temperature of the irrigatingwater (see FIG. 30). Increases in body temperature were presumed to bethe result of warming the circulating blood by the hot water which wasirrigating the end of the nose and viceversa.

The swelling, produced by passing a probe into the brain during hotwater irrigation, was found to be irreversible even after a cold waterirrigation span of IO minutes. This response appeared to be unilaterallyconfined to the side where the injury occured. A rapid increase in CSFP,in addition to the increase obtained during hot water irrigation, wasoften seen shortly after the probe was inserted. In one such experimentthe CSFP began to increase 24 seconds after insertions of the needle andduring the unsuing 45 second the pressure increased by 4 mm/Hg. Sincethe CSFP was monitored in the cysterma magna, it is assumed that thesame CSFP was exerted equally on both cerebral hemispheres. It thusappears that the swelling seen on the right side could not have beencaused by interference with venous drainage from the cerebral cortex tothe dural sinuses. That is, if drainage interference had been the causeboth hemispheres would have been swollen. As it was, the left hemisphereactually appeared to be shrunken. The response of the brain to injury,i.e., an

increase in blood flow to the injured area, appears to be similar to theinflammatory response to injury seen in other parts of the body.

Some conception of the effect of temperature on the dynamics of thecerebral vasculature may be had when considering that CSFP was reducedfrom +7 to 2 mm/Hg in approximately one minute in the face of a presumedpersistent swollen condition in the right cerebral cortex. However, inother trials where the probe was withdrawn, with continued hot waterirrigation, the CSFP remained on the positive side.

The side of the brain probed during cold water irrigation was more firmthan the side probed during hot water irrigation. This was more evidentin the fresh specimens than in those that were embalmed for probe tractstudies. In fact, obtaining a cross section for photography wasdifficult in the fresh specimens because the right side (probed duringhot water irrigation) was very flacid. The left side (probed during coldwater irrigation) was firm, held its shape well and sliced much the sameas liver. The results obtained, relative to inflammation and swelling,by irrigating the alar fold with cold tap water are in agreement, thusfar, with those of other researchers obtained by immersion of theanimals in ice water.

An investigation of the relative amounts of hemorrhage in the probetracts made during hot and cold water irrigation revealed hemorrhage tobe more extensive when hot water was being used. The tract made duringcold water irrigation was evidenced by a very faint gray line dorsal tothe lateral ventricles.

We have concluded that there are two physiological mechanisms which areresponsive to hot and cold water irrigation of the alar fold of themexilloturbinate', namely, the venous temperature control system andcardio-arterial control system both of which have already beendiscussed. Three physiological variables which appear to be amanifestation of these mechanisms are systemic blood pressure (asmeasured in the femoral artery), cerebrospinal fluid pressure (whichreflects cerebral vasodilatation or vasoconstriction) and heart rate. Wehave observed that these variables normally respond in such a way thatthey appear to vary cerebral blood flow.

a. The response of the cerebral vasculature to hot water irrigation isvasodilatation (increase in cerebro spinal fluid pressure) which isusually accompanied by a concurrent increase in femoral arterial bloodpressure and heart rate.

b. The response of the cerebral vasculature to cold water irrigation isvasoconstriction (decrease in cerebrospinal fluid pressure) which isalways accompanied by a concurrent decrease in femoral arterial bloodpressure and usually in a decrease in heart rate.

In general. the animals had a greater sensitivity to changes in watertemperature when anesthetized with urethan than with metofame. However,greater pressure changes were observed when metofame was used.

Swelling occurred when the brain was probed during continued hot waterirrigation while swelling did not occur when the brain was probed duringcontinued cold water irrigation.

The changes in vascular responses and brain temperature noted herein canbe altered by varying the temperature of the skin in the area of thefacial region which overlies and is drained by the dorsal nasal.angularis oculi and facial veins.

in four experiments conducted on three dogs, following endotrachealentubation, the external nares were covered with a cone and sealed toprevent air from flowing through the nasal passages. A needle thermistor(Model HTBl-HN-300, High Temperature lnstruments Corp, Philadelphia,Pa.) was stereotaxically placed in the area where the internal carotidartery emerges from the cavernous sinus. Small thermistors were alsoplaced on the deep surface of both angularis oculi and facial veins. Hotair from a commercial heat gun (Model HG 301 B, Master Appliance Corp.,Racine, Wis.) was directed against the facial region overlying theangularis oculi and facial veins.

RESULTS With each application of heat, the temperatures of the veinsincreased rapidly. This action was always followed by an increase in thetemperature of the area surrounding the stereotaxically placedthermistor site (emergence of internal carotid artery). This lattertemperature increase must also represent an increase in temperature ofthe areas of the brain supplied by internal carotid blood. In arepresentative experiment following a 2 /2 minute heating period, thearea sensed by the stereotaxically-placed thermistor increased by 016 Cin 4% minutes. The temperature then fell by 0.2" C in the next 5minutes.

Experiments on Humans Experiments were conducted on nine separate humanbeings in an attempt to establish that there exists a venous temperaturecontrol system or external heat exchange mechanism at the nasal mucosaas well as a cardio-arterial control system in man. As a result ofourexperiments, described above in connection with dogs, we stronglybelieved that such a mechanism existed, but as has already been pointedout, the researchers Hayward and Baker concluded to the contrary.

ln setting up these experiments thermistors were placed immediatelyadjacent the left and right angularis oculi veins. In some cases(represented by a single asterisk in column 3 of Table ll), thermistorswere placed under the skin alongside the vein. In other cases, (indicated by a double asterick in column 3 of Table ll) thermistors wereplaced on the skin surface directly over the vein. Hence, thetemperature of the blood flowing in the angularis occuli vein throughwhich blood returning from the nasal mucusa flows, was monitored.

It is well known that thinking produces heat in the brain. We hadpostulated that the brain, in regulating its own temperature would fitstcause a cooling of the blood returning from the nasal mucosa through theangularis occuli vein, by means of the venous temperature controlsystem. The cooled venous blood would, in turn, cool the arterial bloodflowing through the carotid artery to the Circle of Willis throughcountercurrent heat exchange in the cavernous sinus (that is, thecardio-arterial control system). It is, of course, impractical tomeasure the temperature of arterial blood flowing to the brain or thetemperature of the brain directly.

The experiment involved stimulating thinking on the part of thesubjects. They were asked to subtract the number seven" consecutively anumber of times, starting with 5,000. That is, the base number fromwhich seven" was subtracted changes as a result of the previoussubtraction. The temperatures indicated in Table ll were recorded on apolygraph recorder manufactured by Grass Instruments. Disturbances wereeliminated to the extent possible from the surroundings of the subjectduring each experiment so as to minimize extraneous mental activityother than that which was induced by the subtraction.

During the conduction of the experiment after the temperature hadleveled off, the subject would be touched or tapped, and this wouldindicate to him to discontinue the mental subtraction process.

A thermistor was also placed alongside the arm vein to see whether therewas any evidence of a more general control mechanism, and this proved tobe negative, as indicated by the data in column of Table II where thesymbol A" indicates the use of an arm thermistor.

Turning then to Table ll, column 1 identifies the subject by number.Column 2 indicates whether the subject was left-handed or right-handed,and column 3 gives the subject's initials, and, as mentioned, indicateswhether thermistors were placed under the skin, alongside the angularisoculi vein (a single asterisk) or whether the thermistors were placedcontacting the skin surface directly over the vein (two asterisks).

Column 4 gives the sex of the subject. Column 5 indicates the left (L)angularis oculi vein, the right (R) angularis oculi vein, and the medianantebrachial (A) vein.

Column 6 indicates the temperature (all tempera tures are in C.) in theassociated vein prior to thinking. Column 7 indicates the maximum changein temperature for the associated sensor during thinking. Column 8indicates the net or cumulative change in temperature noted in column 7for both left and right angularis oculi veins. Column 9 indicates themaximum change in temperature after thinking has terminated, asdescribed above.

ln columns 7-12, the arrows pointing downward indicate a decrease intemperature, and the arrows pointing upward indicate a rise intemperature.

Column 10 indicates the net or cumulative change in temperature of colum9 for both veins. Column 1 l indicates the difference in temperature, ineach vein, between the readings taken before and those taken afterthinking.

Column 12 indicates the net change in column 11 for both veins.

For example, referring to the third subject, from column 7, it isobserved that during thinking there was a maximum change of 05 C. in theleft angularis oculi vein and 0.6" C. in the right angularis oculi vein.After thinking ceased, the temperature in these two veins roserespectively by 0.5 C. and 02 C.

It will be observed that for all subjects, there was a decrease in thetemperature of the angularis oculi vein during thinking, and there was acorresponding increase in temperature after thinking, except in the oneinstance of the left angularis oculi vein of the eighth subject. Thisdata definitely establishes a correlation between temperature change inthe angularis oculi vein and the production of heat in the brain ofahuman being, and therefore, the existence of both a venous temperaturecontrol system and a cardio-arterial control system in the human being.By overriding this system with a cooling or heating fluid applied to thenasal mcuosa, one could produce the same results in a human being ashave been observed in the dog, as discussed above.

Experiments on Horses As has already been explained, Hayward and Baker,in their research, found it necessary to classify subjects into those ofthe internal carotid" and the carotid rete" types. On the basis of theirexperiments, they stated that counter current heat exchange in thecavernous sinus does not occur in species with a single internal carotidartery.

Based upon the above experiment, we have found, to the contrary, thatangularis oculi temperature changes in man bear a good correlation withmental activity.

These experiments with man are considered to be strong evidence thatexternal heat exchange mechanisms, similar to those found in the dog,also are pres ent in man.

Additional experiments have been conducted on horses because of thesimilarity of horses to man particularly in the possession of a singleinternal carotid artery. Other advantages are: (l venous drainage routesfrom the scalp to the ventral petrosal sinus, and (2) a venous drainageroute, by way of a single vessel, from the nasal passage and the face tothe cavernous sinus.

In view of work done by Layton and Sherrington l 9 l 7) on primates, ahypothesis was developed which suggested a relationship between thecirculation system of the scalp and that of the nasal passage and face.It was postulated that, if the brain was concerned with regulating itsown temperature independently, and the horse is similar to the primate,then cooling of the scalp would result in cooling of the blood in theventral petrosal sinus which, in turn, would cool the internal carotidblood in the latter sinus and heating the scalp would have the oppositeeffect. Secondly, it was postulated that the temperature of the bloodentering the cavernous sinus by way of the deep facial vein would changein the opposite direction to thatin the ventral petrosal sinus. If sucha system were operative, the temperature changes would offset oneanother, and the temperature of the blood entering the Circle of Williswould remain unchanged.

We have continuously monitored the temperature of the deep facial veinof the horse during applications of alternate heating and cooling of thescalp. The thermistors were embedded in the connective tissue outsidethe vessel walls, and it is therefore felt that the temperature changesin the blood were greater than those actually recorded A plastic bag wasstrapped to the forehead through which cold and hot water wascirculated, thereby cooling and heating the blood of the scalp. Thetemperature of the circulating water was kept within limits which theponies would tolerate without showing visible signs of discomfort.

It was found, on the basis of experiments with three separate horses,that as the scalp of the horse was cooled, the temperature of the deepfacial vein rose, Further, as the horse 5 scalp was heated, the temperature of the deep facial vein was reduced.

Comparisons of the results obtained in the primate, horse and man,thereby point unmistakably to a functional counter current heat exchangebetween the single internal carotid artery and venous blood. Forexample, venous structure is similar in that a pathway is seen betweenthe scalp and intracranial structures.

The direction of flow appears to be from the scalp through the skull tothe intracranial area because first, the cerebral cortex is cooled andwarmed very rapidly when cold and hot packs are applied in the primate,and secondly, the temperature response of the deep facial vein is theinverse of a temperature change when heat or cold is applied to thescalp of the horse. Further. conditions which increase intracranialtemperature in man (mental activity) and in the horse (hot packs)produce similar responses in the venous path way from the nasal andfacial area of both species-4e, decrease in the temperature of theangularis oculi in nine human subjects (Table II) and a decrease in thetemperature of the facial vein in three out of three horses.

A preferred system for controlling the temperature of the fluid appliedto the nasal mucosa of an animal for purposes of practicing the presentinvention is disclosed in the above-identified copending application,Ser. No. l7l,575.

Having thus described in detail a method and apparatus for practicingour invention. persons skilled in the art will be able to modify certainof the steps disclosed and to substitute equivalent elements for thosewhich have been described while continuing to practice the inventiveprinciples; and it is, therefore, intended that all such modificationsand substitutions be covered as they are embraced within the spirit andscope of the appended claims.

We claim:

I. A method oftreating animals comprising: selecting an animal from theclass consisting those mammals having a single internal carotid arterycarrying blood to the brain; and locally irrigating the region of theface or nasal passage drained by the angularis oculi and other facialveins with a fluid at a predetermined temperature sufficiently differentfrom the normal body temperature of said mammal to override the venoustemperature control system and thereby control the flow of blood to thebrain of said animal.

2. The method of claim 1 wherein said step comprises contacting thenasal mucosa of said animal with said fluid.

3. The method of claim 1 wherein said step comprises continuouslycontacting said region locally only with a gas of controlled temperatureand humidity, the temperature of said gas being different than thetemperature of the ambient atmosphere surronding said animal.

4. The method of claim 1 wherein said step if irrigating comprisesdirecting a stream of cooled fluid against the alar fold of themaxilloturbinate of said animal.

5. The method of claim I wherein said fluid is cooled beneath the normalbody temperature of said animal to thereby induce selective brainhypothermia in said animal.

6. A method of treating animals comprising: selecting an animal from theclass consisting those mammals having a single internal carotid arterycarrying blood to the brain; and locally irrigating the region of theface or nasal passage drained by the angularis oculi and other facialveins with a fluid cooled to a predetermined temperature sufficientlybelow the normal body temperature of said mammal to override the venoustemperature control system and thereby decrease the eerebrospinal fluidpressure, the femoral arterial blood pressure and the heart rate of saidanimal.

7. The method of claim 6 wherein said step comprises contacting thenasal mucosa of said animal with said fluid.

8. The method of claim 6 wherein said step comprises continuouslyflushing the facial skin in said region with a gas having a controlledtemperature and humidity, the temperature of said gas being differentthan the temperature of the ambient environment surrounding saidanimal.

1. A method of treating animals comprising: selecting an animal from theclass consisting those mammals having a single internal carotid arterycarrying blood to the brain; and locally irrigating the region of theface or nasal passage drained by the angularis oculi and other facialveins with a fluid at a predetermined temperature sufficiently differentfrom the normal body temperature of said mammal to override the venoustemperature control system and thereby control the flow of blood to thebrain of said animal.
 2. The method of claim 1 wherein said stepcomprises contacting the nasal mucosa of said animal with said fluid. 3.The method of claim 1 wherein said step comprises continuouslycontacting said region locally only with a gas of controlled temperatureand humidity, the temperature of said gas being different than thetemperature of the ambient atmosphere surronding said animal.
 4. Themethod of claim 1 wherein said step if irrigating comprises directing astream of cooled fluid against the alar fold of the maxilloturbinate ofsaid animal.
 5. The method of claim 1 wherein said fluid is cooledbeneath the normal body temperature of said animal to thereby induceselective brain hypothermia in said animal.
 6. A method of treatinganimals comprising: selecting an animal from the class consisting thosemammals having a single internal carotid artery carrying blood to thebrain; and locally irrigating the region of the face or nasal Passagedrained by the angularis oculi and other facial veins with a fluidcooled to a predetermined temperature sufficiently below the normal bodytemperature of said mammal to override the venous temperature controlsystem and thereby decrease the cerebrospinal fluid pressure, thefemoral arterial blood pressure and the heart rate of said animal. 7.The method of claim 6 wherein said step comprises contacting the nasalmucosa of said animal with said fluid.
 8. The method of claim 6 whereinsaid step comprises continuously flushing the facial skin in said regionwith a gas having a controlled temperature and humidity, the temperatureof said gas being different than the temperature of the ambientenvironment surrounding said animal.